¹⁷⁷Lu-Labeled Anticlaudin 6 Monoclonal Antibody for Targeted Therapy in Esophageal Cancer

Abstract

Advanced or metastatic esophageal cancer (EC) is associated with poor prognosis, necessitating new and effective treatment methods. We assess whether claudin 6 (CLDN6) is a useful target for the imaging and radiopharmaceutical therapy of EC using a novel pair of radioactive nuclides, ⁸⁹Zr and ¹⁷⁷Lu. <b>Methods:</b> CLDN6 messenger RNA expression was evaluated in 2 EC datasets (<i>n</i> = 436) and through a retrospective analysis of 109 patients with EC. We then used an anti-CLDN6 monoclonal antibody (IMAB027) labeled with ⁸⁹Zr and ¹⁷⁷Lu ([⁸⁹Zr]Zr-DFO-IMAB027 and [¹⁷⁷Lu]Lu-DOTA-IMAB027) for PET imaging and therapy, respectively. Imaging and biodistribution analyses were performed using the TE-1-CLDN6 xenograft model. Finally, the therapeutic potential of [¹⁷⁷Lu]Lu-DOTA-IMAB027 was evaluated in both the TE-1-CLDN6 and the CLDN6-PDX (patient-derived xenograft) models. <b>Results:</b> CLDN6 messenger RNA expression was elevated in EC compared with healthy esophageal tissues. The CLDN6 expression rate was 0 in healthy esophageal tissue but was 79.8% in EC tissue. The [⁸⁹Zr]Zr-DFO-IMAB027 showed the ability to effectively image EC xenografts with high CLDN6 expression. In the TE-1-CLDN6 model, there was a significant difference in tumor volume between the 11.1-MBq [¹⁷⁷Lu]Lu-DOTA-IMAB027 treatment group and the control group (<i>P</i> &lt; 0.001). The tumor growth inhibition rate in the 11.1-MBq [¹⁷⁷Lu]Lu-DOTA-IMAB027 group was 101.74%. In the PDX model, significant differences in tumor volume were observed among all [¹⁷⁷Lu]Lu-DOTA-IMAB027 treatment groups and the control group (<i>P</i> &lt; 0.05). Specifically, the tumor growth inhibition rate of the 11.1-MBq [¹⁷⁷Lu]Lu-DOTA-IMAB027 group was 79.04%, whereas that of the 3.7-MBq group was 77.20%. However, the difference in efficacy between the high-dose and low-dose groups was not statistically significant (<i>P</i> &gt; 0.05). <b>Conclusion:</b> The differential expression of CLDN6 between tumors and the normal esophagus shows its potential as a diagnostic and therapeutic target for EC. The radiotracer [⁸⁹Zr]Zr-DFO-IMAB027 showed high contrast when visualizing CLDN6-expressing xenografts for PET imaging, and [¹⁷⁷Lu]Lu-DOTA-IMAB027 induced rapid tumor regression in both the TE-1-CLDN6 and the CLDN6-PDX models. This research has implications for improving the radioligand diagnosis and treatment of EC.

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